Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
  • C07F9/4808—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof the acid moiety containing a substituent or structure which is considered as characteristic
  • C07F9/4816—Acyclic saturated acids or derivatices which can have further substituents on alkyl

Definitions

• the present invention relates to a new process for the synthesis of alkyl phosphinic acids, and more particularly to a coupling reaction between an alkyl halide and a hypophosphorous acid derivative by a radical initiated reaction.
• the invention also relates to compounds obtainable by the process of the invention.
• a radical initiated reaction between a hypophosphorous acid and an alkene is disclosed in Deprele, S., et al, J. Org. Chem., 2001, 66, 6745-6755.
• the reaction is a radical addition of hypophosphites to olefins and the radical reaction is initiated by trialkylboranes and oxygen.
• Winqvist A., et al., Eur. J. Org. Chem., 2002, 1509-1515, describe, inter alia, synthesis of phosphinic acids from alkyl halides and bis(trimethylsilyl)-hypophosphite.
• the publication describes the influence of the temperature during the reaction.
• WO 01/42252 discloses aminopropylphosphinic acids and the, synthesis thereof. The synthesis described is a stepwise reaction starting from a substituted serine compound.
• initiators in the collection of suitable radical initiators require heat addition for initiating the reaction.
• oxygen can be used as an initiator for a radical reaction.
• some of the hypophosphorous acid derivatives are pyrophoric and therefore oxygen is not a suitable initiator.
• One such example is the hypophosphorous acid derivative bis-trimethylsilyl hypophosphite.
• Chemical radical initiators would be possible for initiating the reaction between an alkyl halide and a hypophosphorous acid derivative. Most often, when such initiators are used, the reaction is started by raising the temperature of the reaction mixture. However, temperature is also a critical parameter for reduction of the amount of by-products, the lower temperature the lower amount of by-products.
• the present invention provides a new process for the preparation of alkyl phosphinic acids and salts thereof. More particularly, the present invention is directed to a new process for the preparation of an alkyl phosphinic acid, whereby an alkyl halide is reacted with a hypophosphorous acid derivative by a radical initiated reaction.
• the alkyl phosphinic acid is synthesised by a process comprising the following steps: a) forming a hypophosphorous acid derivative ; b) adding an alkyl halide to the product of step a); and c) initiating the radical reaction.
• R 1 is selected from a Ci-C] 6 alkyl optionally substituted or interrupted by one or more substituents selected from linear or branched Ci-Ci 0 alkyl, cyclic C 3 -C 6 alkyl, aryl, heteroaryl, hydroxy, oxo, mercapto, Cj-Cio alkoxy, Ci-C 10 thioalkoxy, fluorine or chlorine; or
• R 1 is selected from a Ci-Ci 6 alkylamine optionally substituted or interrupted by C 1 -C 10 alkyl, cyclic C 3 -C 6 alkyl, aryl, heteroaryl, hydroxy, mercapto, Cj-C 10 alkoxy, Ci-C 10 thioalkoxy, fluorine or chlorine;
• reaction being radical initiated.
• R 2 is selected from a Ci-Cio-alkyl optionally substituted or interrupted by one or more substiruents selected from C 1 -Ci 0 alkyl, cyclic C 3 -C 6 alkyl, aryl, heteroaryl, hydroxy, oxo, mercapto, C 1 -Ci 0 alkoxy, Ci-Ci 0 thioalkoxy, fluorine or chlorine; or a Ci-Cio-alkylamine optionally substituted by one or more substiruents selected from Ci-
• R 3 and R 4 are each and independently selected from a Cj-C ⁇ -alkyl optionally substituted or interrupted by one or more substituents selected from CrC 6 alkyl, cyclic C 3 -C 6 alkyl, aryl, heteroaryl, hydroxy, oxo, mercapto, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, fluorine or chlorine; or a Ci-C 6 alkylamine optionally substituted or interrupted by one or more substituents selected from Ci-C 10 alkyl, aryl, heteroaryl, hydroxy, mercapto, Ci-Cio alkoxy, C 1 -CiO thioalkoxy, fluorine or chlorine; or hydrogen;
• R 2 , R 3 and R 4 are each and independently defined as above, and X represents a halogen selected from bromide or iodine;
• reaction being radical initiated.
• R 5 and R 6 are each and independently selected from hydrogen; fluorine; chlorine; OR 1 ' ; N(R 12 XR 13 ); or a C 1 -C 10 alkyl optionally substituted by hydroxy, fluorine, chlorine, mercapto, C 1 -C 10 alkoxy, C 1 -C 10 thioalkoxy or aryl;
• R 7 and R 8 are each and independently selected from hydrogen; fluorine; chlorine; OR ; N(R 12 )(R 13 ); oxo; or a C 1 -C 1O alkyl optionally substituted by hydroxy, fluorine, chlorine, mercapto, C 1 -C 1 Q alkoxy, C 1 -C 10 thioalkoxy or aryl;
• R 9 and R 10 are each and independently selected from hydrogen; fluorine; chlorine; C 1 -C 10 alkyl; aryl; OR 1 ] ; or N(R 12 )(R 13 );
• R 11 is selected from C(O)R 14 ; Ci-Ci 0 alkyl; hydrogen; or from an oxygen protecting group such as acetate, benzoate, benzyl, tert-butyl dimethylsilyl, triethyl silyl or triphenyl methane;
• R 12 and R 13 are each and independently selected from a Ci-Cio-alkyl; aryl; heteroaryl; hydrogen; or a nitrogen-protecting group such as tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl; a benzoyloxycarbamate or phtalimide;
• R 14 is selected from a linear or branched C 1 -C] 0 alkyl optionally substituted or interrupted by C 1 -C 6 alkyl, aryl or heteroaryl; or R 14 is selected from a linear or branched Ci-Cio alkoxy;
• R 15 and R 16 are each and independently selected from hydrogen; fluorine; chlorine; OR 21 ;
• R 17 and R 18 are each and independently selected from hydrogen; fluorine; chlorine; OR 21 ; N(R 22 XR 23 ); oxo; or a C 1 -C 10 ahcyl optionally substituted by hydroxy, mercapto, C 1 -C 10 alkoxy, Ci-C 10 thioalkoxy or aryl;
• R 19 and R 20 are each and independently selected from hydrogen; fluorine; chlorine; C 1 -C 1O alkyl; aryl; OR 11 ; or N(R 12 ) (R 13 );
• R 21 is selected from C(O)R 24 , hydrogen, a C 1 -Ci 0 alkyl optionally substituted by hydroxyl, fluorine or chlorine; or an oxygen protecting group such as acetate, benzoate, ben ⁇ yl, tert-butyl dimethylsilyl, triethyl silyl; or triphenyl methane;
• R and R are each and independently selected from a Ci-Cio-alkyl; aryl; heteroaryl; hydrogen; or a nitrogen-protecting group such as tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl; a benzoyloxycarbamate, or phtalimide;
• R 24 is selected from a linear or branched C]-Ci 0 alkyl optionally substituted or interrupted by Ci-C 6 alkyl, aryl, heteroaryl or R 24 is selected from a linear or branched Ci-C] 0 alkoxy;
• X is a halogen selected from iodide or bromide
• reaction being radical initiated.
• R 25 is selected from hydrogen; a linear or branched Q-Qo-alkyl; a linear or branched C 1 - Ci 0 -alkoxy; fluorirle or chlorine;
• R 26 is selected from hydroxy; mercapto; fluorine; chlorine; oxo; a Q-Cio-alkoxy or • C(O)R 29 ;
• R 27 is selected from hydrogen or a C 1 -CO alkyl optionally substituted by hydroxy, mercapto, Q-Qo-alkoxy, C 1 - Cio-thioalkoxy or aryl;
• R 28 is selected from hydrogen, C(O)R 29 or a Ci-Cio-alkyl optionally substituted with aryl;
• R 29 is selected from a linear or branched C]-C 10 alkyl optionally substituted or interrupted by Ci-C 6 alkyl, aryl, and heteroaryl; or R 29 is selected from a linear or branched C]-C 1 O alkoxy;
• R 30 is selected from hydrogen; a linear or branched Ci-Cio-alkyl; a linear or branched Cr Cio-alkoxy; fluorine or chlorine; R 31 is selected from hydroxy; mercapto; fluorine; chlorine; oxo; Q-C 10 -alkoxy or C(O)R 34 ;
• R 32 is selected from hydrogen; or a Ci-Q-alkyl optionally substituted by hydroxy, mercapto, Q-Qo-alkoxy, CrCjo-thioalkoxy or aryl;
• R 33 is seleceted from hydrogen, C(O)R 34 ; or Ci-Cio-alkyl optionally substituted by aryl;
• R 34 is selected from a linear or branched Cj-C 1O alkyl optionally substituted or interrupted by C 1 -C 6 alkyl, aryl, or heteroaryl; or R 34 is selected from a linear or branched Ci-C 1 O alkoxy;
• X is a halogen selected from iodide or bromide
• reaction being radical initiated.
• R 25 is hydrogen; R 26 is fluorine; R 27 is hydrogen; R 28 is C(O)R 29 ; and R 29 is tert-butoxy;
• R 30 is hydrogen
• R 31 is fluorine
• R 32 is hydrogen; R 33 is C(O)R 34 ;
• R 34 is tert-butoxy
• X is iodide; with a hypophosphorous acid derivative, said reaction being radical initiated.
• hypophosphorous acid derivative used for the synthesis of a phosphinic acid is a compound or formula IX
• R and R are each and independently selected from a linear or branched Ci-C 1 O alkyl or Si(R 37 ) 3 ;
• R » 3"7 is a Ci-C 6 alkyl.
• hypophosphorous acid derivatives are suitable for the radical initiated reaction, for example, compounds of formula X
• R 38 is selected from hydrogen; methyl or phenyl; and R 39 is a linear or branched Ci-C 3 alkyl.
• hypophosphorous acid derivative of formula XI may be suitable for the reaction of the invention OSi R 40 ⁇
• R 40 is a linear or branched C 1 -C5 alkyl.
• the hypophosphorous acid derivative bis(trimethyl silyl)hypophosphite is formed.
• the bis(trimethylsilyl)hypophosphite may be formed in different ways, for example, by reacting ammonium hypophosphite with trimethyl silyl chloride in the presence of an amine, such as diisopropyl ethyl amine (DIPEA), N-methylmorpholine or triethylamine, or by reacting ammonium hypophosphite with hexamethyl disilazan.
• DIPEA diisopropyl ethyl amine
• N-methylmorpholine or triethylamine or by reacting ammonium hypophosphite with hexamethyl disilazan.
• C 1 -Ci 6 alkyl as used throughout this specification is intended to include linear, branched or cyclic C 1 -Ci 6 alkyl.
• Examples of Ci-Ci 6 alkyl are, but are not limited to, Cj-C 6 alkyl, methyl, ethyl, propyl, n-propyl, isopropyl, cyclic propyl, butyl, iso-butyl, sec-butyl, tert-butyl, cyclic butyl, pentyl, cyclic pentyl, hexyl and cyclic hexyl.
• Ci-C 1 O alkyl as used throughout this specification includes linear, branched or cyclic Ci-Cio alkyl.
• Examples of Ci-Ci 0 alkyl include, but are not limited to, Ci-C 6 alkyl, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl.
• cyclic C 3 -C 6 alkyl as used throughout this specification is intended to inlude cyclic propyl, cyclic butyl, cyclic pentyl, and cyclic hexyl.
• alkoxy denotes an O-alkyl, wherein alkyl is as defined above.
• C 1 -CiO alkoxy as used throughout this specification includes linear, branched or cyclic CrC 10 alkoxy. Examples of Ci-C 10 alkoxy include, but are not limited to, Ci-C 6 alkoxy, methoxy, ethoxy, propoxy, n-propoxy, and tert-bntoxy.
• Ci-Ci 0 thioalkoxy denotes a S-alkyl, wherein alkyl is as defined above.
• Ci-Ci 0 thioalkoxy as used throughout this specification includes linear, branched or cyclic Ci-Ci 0 thioalkoxy. Examples of Ci-Ci 0 thioalkoxy include, but are not limited to, Ci -C 6 thioalkoxy, thiomethoxy, thioethoxy, thiopropoxy, n-thiopropoxy.
• Ci-C 16 alkylamine as used throughout this specification includes linear, branched or cyclic Ci-Ci 6 alkylamine optionally substituted or interrupted by C 1 -Ci O alkyl, aryl, hydroxy, mercapto, C 1 -C 7 alkoxy, Ci-C 7 thioalkoxy, fluorine or chlorine.
• aryl as used throughout this specification means an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
• the aryl may be substituted by Ci-C 6 alkyl or halogens such as fluorine, chlorine and bromide.
• heteroaryl as used throughout this specification means an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
• the heteroaryl may be substituted by Ci-C 6 alkyl or halogens such as fluorine, chlorine, and bromide
• a suitable way of initiation radical reaction is by irradiation.
• a suitable source of irradiation is ultraviolet light, i.e. UV-irradiation.
• the radical reaction can be performed by the radiation from sunlight, but for a more efficient and controllable initiation of the reaction, an ultraviolet source may be used.
• the spectra of wavelengths for ultraviolet light typically extend from 40 nm to 400 nm. There are possibilities to make the initiation more specific, as a choice of a specific wavelength within this range is possible. The wavelength is an important parameter required by, for example, the substrates selected.
• ultraviolet irradiation as a radical initiator, a spectra of sources of ultraviolet light is available, for example, low pressure mercury lamp or medium pressure mercury lamp. Thus, depending on the substrates selected this might be an important parameter for an efficient reaction.
• An example of a specific ultraviolet irradiation source is a low-pressure mercury lamp, which produces an ultraviolet light with a wavelength of approximately 254 nm.
• the size and shape of the reaction vessel may require different arrangements for illuminating the reaction mixture.
• the illuminated surface area of the reaction mixture has been found to be a critical aspect, regarding efficiency, when using ultraviolet irradiation.
• the effect of the irradiation is limited to a few millimetres in the depth of the reaction mixture. Therefore, for a more efficient reaction the aim is to illuminate as large surface area as possible. Irradiation of the reaction mixture can be performed in different ways in order to illuminate as large surface area as possible.
• the position of the UV-source may therefore be critical.
• the source may be placed in the reaction mixture; the reaction mixture may be irradiated by placing the UV-source above the reaction vessel; or alternatively the walls of the reaction vessel may be irradiated or the reaction mixture may be pumped through a tube with a UV-source in the middle.
• the synthesis of the phosphinic acids according to the present invention is performed at temperatures below room temperature, i.e. at a temperature below 20 0 C.
• the effect of having a lower temperature is that the various side reactions and the amont of by-products limiting the yieald of the reaction are reduced.
• the reaction mixture is held at a temperature of 0 0 C.
• the reaction mixture is held at a temperature below -20 0 C.
• Dehalogenation is a side reaction, which can occur. However, the dehalogenation is suppressed at lower temperature, and thus, the production of the sideproducts is suppressed.
• alkyl phosphinic acid which has been produced according to the present invention by adding the alkyl halide, which has been dissolved in a solvent, to a cooled solution comprising the hypophosphorous derivative in an inert environment, i.e. an environment free from oxygen attained by using nitrogen or argon.
• the reaction can be described in the following general way: Alkyl halide + hypophosphorous acid derivative ⁇ alkyl phosphinic acid
• the components for forming the hypophosphorous acid derivative i.e. the hypophosphite group, are, for example, ammonium hypophosphite and hexamethyldisilazan, ammonium hypophosphite, diisopropylethyl amine and trirnethylsilyl chloride. They are mixed in a vessel until the reaction is completed, the reaction mixture is then cooled and kept in an environment free from oxygen.
• the first step of the synthesis for obtaining alkylphosphinic acids is the formation of bis(trimethylsilyl)hypophosphite.
• the formation of the hypophosphorous acid derivative just before the addition of the alkyl halide is an advantage since the hypophosphorous acid derivative is highly pyrophoric.
• the alkyl halide is then added and the reaction is thereafter initiated by irradiation with ultraviolet light.
• the completion of the reaction is measured by, for example, HPLC or
• a neutralisation of the hydrogen halide formed during the reaction can be performed by having a base present during the synthesis of the phosphinic acid.
• the base is suitably an amine such as, but not limitied to, hexamethyldisilazan, N-methylmorpholine, triethylamine, or diisopropyl ethyl amine (DIPEA).
• reaction is conducted in non-polar or polar organic solvent, for example, toluene, methylene chloride, tetrahydrofuran, acetonitril or in a mixture thereof.
• non-polar or polar organic solvent for example, toluene, methylene chloride, tetrahydrofuran, acetonitril or in a mixture thereof.
• the compound formed is recovered by extraction in a polar solvent such as ethylacetate, isopropanol, n-butanol or a mixture thereof.
• a polar solvent such as ethylacetate, isopropanol, n-butanol or a mixture thereof.
• the compounds synthesised according to the claimed process of the present invention can form salts with bases.
• Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or those with ammonia or organic amines.
• the process according to the present invention is an efficient as well as an economical process for the preparation of alkylphosphinic acids. The following examples will further illustrate the invention, but is not intended to limit the scope of the invention as described herein or as claimed below.
• the following examples show the synthesis of (2i?)-3-[(tert-butoxycarbonyl)amino]-2- fluoropropyl phosphinic acid from a reaction of an alkyl halide and the hypophosphorous acid derivatives bis-(trimethylsilyl) hypophosphite and hexamethyldisilazan.
• the examples are performed in order to show the effect of the initiation of the radical reaction, i.e. the reactions are performed in the presence or in the absence of a radical initiator.
• synthesis of an alkylphosphinic acid in larger scale according to the invention is described.
• Bis-(trimethylsilyl) hypophosphite formed with trimethyl silyl chloride/ diisopropyl ethylamine (DIPEA).
• Example IA Reaction initiated with ultraviolet light.
• An inert slurry was formed by mixing 1.4 g of ammonium hypophosphite (16.4 mmol) in 6 mL of toluene in a nitrogen atmosphere. 3.3 mL of diisoproylethyl amine (19.7 mmol) was added, followed by 4.6 mL of trimethylsilylchloride. The reaction mixture was held with stirring for 3 hours at room temperature. 1 g of fer ⁇ -butyl (2ft)-2-fluoro-3-iodo- propylcarbamate (3.3 mmol) dissolved in 2 mL of toluene was then added. The reaction mixture was irradiated with ultraviolet irradiation (6W low-pressure mercury lamp). The reaction was completed 3 hours after the start of reaction.
• Example 2A reaction initiated by ultraviolet irradiation.
• the reaction was detected completed (by LC) after 3 h.
• the reaction was quenched by addition of 500 mL, 12.5 % NH 4 OH.
• a two-layer slurry was formed, which was allowed to obtain room temperature over night. Two clear phases were obtained the next day. The phases were separated; the water phase was added back to the reactor while the organic phase was discarded. The water phase was extracted two times with n-butanol (2x200mL). The organic phases were combined and concentrated to approximately 100 mL. n-Butanol (100 mL) was added the formed slurry and the resulting slurry was heated to 60 0 C.
• Example 4B Synthesis of phenethyl phosphinate ammonium salt without ultraviolet irradiation
• Example 4A The reaction according to Example 4A was repeated without irradiation with the 125 W 5 UV-lamp. After 20 hours the reaction was quenced and worked-up as above to afford 220 mg. Yield: 20%.
• Example 5B Synthesis of of cyclohexyl phosphinate ammonium salt without Ultraviolet irradiation.
• Cyclohexyl iodine (0.80 mL, 6 mmol) dissolved in methylene chloride (3 mL) was added to a solutiuon of bistrimethylsilyl hypophosphite prepared as in example 2a (4 equivalents) at 70 0 C.
• the reaction was quenched with NH 4 OH/ water, 1:1 (6 mL) and worked up as in example 5 A after 11 days to afford 170 mg of white salt. Yield: 17 %.
• Example 6A Synthesis of 1-adamantyl phosphinic acid with ultraviolet irradiation.
• Example 6B Synthesis of 1-adamantyl phosphinic acid without ultraviolet irradiation.
• 1-ioddadamantane (1.61 g, 6 mmol) dissolved in toluene (3 mL) was added to a solution of bistrimethylsilyl hypophosphite prepared as in example 2a (4 equivalents) at 40 0 C.
• the reaction was quenched with NH 4 OH/ water, 1 : 1 (6 mL) and worked up as in example 6A after 6 days to afford 90 mg of white salt. Yield: 7 %.
• Ammonium hypophosphite 100 kg, 1204 moles, 5.0 equiv.
• toluene 305 kg, 351 L, 4.8 rel vol
• the mixture was heated to 97 0 C and hexamethyldisilazan (HMDS, 270.8 kg, 1678 moles, 7.0 equiv.) was charged slowly (13.5 hours) while keeping the temperature at 96 ⁇ 3 °C.
• HMDS hexamethyldisilazan

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